Neurons require glucose uptake and glycolysis in vivo

Huihui Li, Caroline Guglielmetti, Yoshitaka J. Sei, Misha Zilberter, Lydia M. Le Page, Lauren Shields, Joyce Yang, Kevin Nguyen, Brice Tiret, Xiao Gao, Neal Bennett, Iris Lo, Talya L. Dayton, Martin Kampmann, Yadong Huang, Jeffrey C. Rathmell, Matthew Vander Heiden, Myriam M. Chaumeil, Ken Nakamura

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Neurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy remains unclear. Using metabolomics, we show that human neurons do metabolize glucose through glycolysis and can rely on glycolysis to supply tricarboxylic acid (TCA) cycle metabolites. To investigate the requirement for glycolysis, we generated mice with postnatal deletion of either the dominant neuronal glucose transporter (GLUT3cKO) or the neuronal-enriched pyruvate kinase isoform (PKM1cKO) in CA1 and other hippocampal neurons. GLUT3cKO and PKM1cKO mice show age-dependent learning and memory deficits. Hyperpolarized magnetic resonance spectroscopic (MRS) imaging shows that female PKM1cKO mice have increased pyruvate-to-lactate conversion, whereas female GLUT3cKO mice have decreased conversion, body weight, and brain volume. GLUT3KO neurons also have decreased cytosolic glucose and ATP at nerve terminals, with spatial genomics and metabolomics revealing compensatory changes in mitochondrial bioenergetics and galactose metabolism. Therefore, neurons metabolize glucose through glycolysis in vivo and require glycolysis for normal function.

Original languageEnglish
Article number112335
JournalCell Reports
Volume42
Issue number4
DOIs
StatePublished - Apr 25 2023

Keywords

  • CP: Neuroscience
  • bioenergetics
  • brain energy
  • galactose metabolism
  • glucose transporter
  • glycolysis
  • hyperpolarized magnetic resonance spectroscopic imaging
  • metabolomics
  • neuronal glucose metabolism
  • pyruvate kinase

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